Disturbed folate metabolism is also a risk factor for blood clots (thromboembolism) and increased risk of all cancers.

5MTHF is the Active Form of Folate

Folate itself cannot enter the brain. It must first attach to Folate Receptors (FR) in the choroid plexus and then be converted to the active form, MTHFR, which then may cross the blood brain barrier to enter the brain tissue.

The active form of folate is 5MTHF, (also called 5-Methyl-Tetra Hydro-Folate) This form of the vitamin can easily cross the blood brain barrier, enter the brain and promote neurotransmitter production.

Folate Receptor Antibodies

In Autism, the Folate Receptor is non-functioning because of auto-antibodies. This is a form of autoimmune disease in which an immune response is mounted against the Folate Receptor. This is a bad thing because the Folate Vitamin is not working and cannot get into the brain where it is needed.

75% of Autistic Children Have Folate Receptor Antibodies

Dr. Frye’s study found that Folate Receptor Antibodies were present in 75% of the 93 autistic children studied. In 16 children in which spinal fluid samples were studied, the presence of Folate Receptor Antibodies correlated with reduced cerebrospinal fluid 5-MTHF levels.

Treatment with Activated Folate

The autistic children were treated with up to 50 mg per day of Leucovorin over 4 months. This is an activated folate vitamin. One third of treated children were deemed “Moderate” to “Much Improved” in verbal communication, receptive and expressive language, attention and stereotypical behavior. The authors recommended empiric treatment of all autistic children with activated Folate supplements ( Such as 5mg caps 5MTHF from Thorne)

Leucovorin is Folinic acid, a 5-formyl derivative of Tetra-Hydo-Folate. Regular folic acid is not effective and not recommended for MTFHR patients. Also available is prescription Deplin, a 15 mg methyl folate tablet.

A Major Breakthrough

This is truly a major breakthrough in our understanding of Autism, and other neuropsychiatric disorders associated with disrupted Folate metabolism.

Previous Work in 2007 Also Showed Similar Findings

This new study by Dr Frye confirms a previous 2007 study by Dr Ramaekers from Belgium who found Folate receptor autoimmunity and cerebral folate deficiency in 23 of 25 autism patients.

MTHFR Genetic Mutation

Another patient group with disrupted folate metabolism is the MTHFR Mutation. In this genetic mutation, conversion of Folate to its active form (5MTHF) is reduced by 20-70 % efficiency, depending on whether the mutation is heterozygous or homozygous.

These patients have a genetic inability to utilize Folate, since they cannot convert folate to its active form, or conversion is inefficient. This MTHFR genetic mutation is associated with various neuropsychiatric conditions such as Attention Deficit Disorder, (ADHD), Depression and a host of others as you might expect from the inability of the brain to produce sufficient quantities of neurotransmitters, Serotonin, Dopamine and Norepinephrine.

Poly Drug Psych Meds for MTHFR ??

Without realizing there is a Folate problem, the mainstream medical system will treat many of these MTHFR patients with a poly-drug approach with Adderal, Ritalin, SSRI antidepressants, and Atypical Anti-psychotics like Respiradol and Zyprexa. However, none of these drugs address the underlying cause which is a Folate conversion problem.

As these patients need Methyl-Folate, the correct treatment for these patients is not a Psycho-Stimulant Drug which obviously contains no Methyl-Folate. If the MTHFR genetic mutation is present, these patients should be given 5-Methyl-Tetra-Hydro-Folate (the active form of the vitamin) which is widely available at the health food store without a prescription.

Routine Testing for MTHFR

We routinely test all patients for this genetic mutation called MTFR Reductase available through Quest, andLabcorp.

Patients may also self-test with anonymous online genetic testing with a home test kit ordered online.

1) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578948/
Mol Psychiatry. 2013 Mar;18(3):369-81. doi: 10.1038/mp.2011.175. Epub 2012 Jan 10.
Cerebral folate receptor autoantibodies in autism spectrum disorder. Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Source Department of Pediatrics, Arkansas Children’s Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock,
Abstract Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.

2) http://www.ncbi.nlm.nih.gov/pubmed/18461502
Neuropediatrics. 2007 Dec;38(6):276-81.
Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits.
Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV.SourceDivision of Child Neurology, University Hospital Liège, Belgium.Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respect to folate transport across the blood-CSF barrier. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits. Early detection of FR autoantibodies may be a key factor in the prevention and therapeutic intervention among this subgroup of patients with autism.

CNS Spectr. 2009;16:1(Suppl 2):1-7 Dr. Farah is chief of Psychiatry at High Point Regional Health Systems, High Point NC, and is clinical faculty at Wake Forest University, Winston-Salem NC. Disclosures: Dr. Farah serves as consultant to and receives honoraria from Pamlab.Abstract

Major depressive disorder (MDD) is a debilitating and often recurrent illness. An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as partial or non-responders. Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This Expert Review Supplement reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations.

Supplementation with folate may help reduce depressive symptoms. Folate, a naturally occurring B vitamin, is needed in the brain for the synthesis of norepinephrine, serotonin, and dopamine. Three forms of folate are commonly used: folic acid, 5-methyltetrahydrofolate (5-MTHF) (also known as methylfolate and L-methylfolate), and folinic acid. Some forms may be more bioavailable than others in patients with a genetic polymorphism and in those who take particular medications or use alcohol. Folic acid augmentation in depressed patients may reduce residual symptoms. The 5-MTHF formulation indicated efficacy as adjunctive therapy or monotherapy in reducing depressive symptoms in patients with normal and low folate levels, improving cognitive function and reducing depressive symptoms in elderly patients with dementia and folate deficiency, and reducing depressive and somatic symptoms in patients with depression and alcoholism. Adjunctive folinic acid reduced depressive symptoms in patients who were partially responsive or nonresponsive to a selective serotonin reuptake inhibitor. Evidence for the efficacy of folate in improving cognitive symptoms is equivocal, but most studies used folic acid. Although the studies reviewed have limitations and, historically, concerns have been raised about the role of folate in increasing cancer risk, masking B(12) deficiency, and worsening depressive symptoms, folate is generally well tolerated, and 5-MTHF may be less likely to incur some of these risks. Several forms of folate appear to be safe and efficacious in some individuals with major depressive disorder, but more information is needed about dosage and populations most suited to folate therapy.(pdf file downloaded) my pdf download area

Depression is common – one-fourth of the U.S. population will have a depressive episode sometime in life. Folate deficiency is also relatively common in depressed people, with approximately one-third of depressed individuals having an outright deficiency. Folate is a water-soluble B-vitamin necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, epinephrine, and dopamine. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), participates in re-methylation of the amino acid metabolite homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters. Without the participation of 5-MTHF in this process, SAMe and neurotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression. SAMe supplementation was shown to improve depressive symptoms. 5-MTHF also appears to stabilize, enhance production of, or possibly act as a substitute for, tetrahydrobiopterin (BH4), an essential cofactor in monoamine neurotransmitter biosynthesis. There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment for depression related to folate deficiency; however, the studies that have been conducted are promising. Depressed individuals with low serum folate also tend to not respond well to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Correcting the insufficiency by dosing folate along with the SSRI results in a significantly better antidepressant response.

6) http://addbringingbalance.blogspot.com/An ADD Family Success Story. MTHFR mutation addressed
An ADD family story with a drug free solution. I have 4 children ranging in age from 11-26 with ADD. I’m sharing my experience and solutions, hopefully to bring balance into the lives of ADD families Here is the name of the blood test to order: MTHFR, DNA Mutation.

Methylenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes in human physiology, having influence on at least as many biochemical processes as it has syllables in its nearly unpronounceable name.

Deficiencies in production or function of this enzyme have been associated with increased risk of myocardial infarction, stroke, venous thrombosis, several types of cancer, congenital defects, inflammatory bowel disease, and several neuropsychiatric conditions. In practice, MTHFR function is an important predictor of predispositions to chronic disease states, and interventions aimed at optimizing MTHFR function can often be preventive or therapeutic

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For those wanting a better understanding of why we become stressed (physical, mental, chemical) and can’t return to “normal” due to lack of methylation, I recommend you read Dr Jack Tips’ article on Methylation at [http://www.anma.org/pdf/Methylation_by_Dr_Jack_Tips_Complete_and_Illustrated_Article.pdf] .
B6-B9-B12 is part of the Folate pathway, and when the latter is disrupted, Autism is one possible outcome.

Thanks for sharing this! This may have implications for me and my daughter, because I have a known mthfr mutation and low folate levels and depression. These dots have never been connected. I was tested for mthfr after a severe miscarriage and I struggled with folate deficiency throughout that pregnancy and subsequent attempts at fertility treatments. My daughter has severe infant onset autism, but I have never had any testing done for mthfr or for the antibodies. I am wondering if I should just supplement right away or show this to her doctor. I wonder if can even help her because she is older now… she is 19. Do you think this is worthfurther investigation?

With respect to Dr. Frye and his credibility, he is an extremely credible source on autism research, autism biochemistry, and supplements. He has 32 papers in pubmed by my count. Many represent significant break thoughs. His most recent one was published earlier this month and is on folate receptor alpha antibodies in autism which connects autoimmunity with functional vitamin deficiencies and strikes me as an important area of research. You can find it here if you are interested: http://www.ncbi.nlm.nih.gov/pubmed/27013943.

In addition based on my limited time with Dr. Frye, he is a very generous person and is truly trying to help those affected. Despite the fact that his time is very valuable, he spent about forty minutes of it answering my questions. We need more people like him doing autism research.

With respect to your concern on a particular grant being terminated for “non-compliance”, I have no idea of the specific cause. You seem to be suggesting that there is something of critical importance behind this. I do not know whether your assumption is correct or not, but it seems to me that there may also be technical explanations for the status of the grant such as misfiled paper work or paper work not filed before some deadline.

In any case, if there is something of substance in the interview I conducted with Dr. Frye that you object to, in my opinion you should say so rather than making insinuations. If you are interested, I also have another interview up with a Dr. Robert Hendren on methyl-B12 available here (http://autismrc.com/).

I didn’t see any links or recommendations on pediatric doses of the 5-mthf supplements. I have two MTHFR genes, we haven’t had my son tested as pretty much all the doctors here seem to think that’s just Made up stuff. Not going into what doctors have said but my son is autistic and I would love to get info on vitamins and minerals to introduce. He takes Doterra (all natural sources) now and I have seen improvement but I would love to break him out of autism completely. I am convinced its because of our Auto Immune diseases that is like he is especially when I was un diagnosed celiac when pregnant and very ill. He has Celiac and I have Celiac and MTHFR.